D797N
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialAspartate → Asparagine at position 797. ClinVar Conflicting including monogenic hearing loss + DFNA6. AlphaMissense 0.556 (borderline), ΔΔG -0.02 (neutral). Same position as D797V — second substitution at 797.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | E794 | E794 | Preserved |
| Hydrogen bond | T799 | T799 | Preserved |
| Hydrogen bond | K800 | K800 | Preserved |
| Polar contact | E794 | E794 | Preserved |
| Polar contact | T799 | T799 | Preserved |
| Polar contact | K800 | K800 | Preserved |
| Van der Waals | — | T799 | Gained |
| Hydrophobic | K800 | K800 | Preserved |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
- pLDDT 64.88 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Hearing loss, inheritance unstated (inheritance not specified); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Optic atrophy / optic neuropathy (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Monogenic hearing loss; Rare genetic deafness
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 797 same neighbors as D797V: VAL798 (2.4 Å), ASP796 (2.4 Å), GLU794 (4.2 Å), THR799 (4.3 Å).
D797N conserves the local geometry but eliminates the charge. The D796-D797-E794 charged cluster loses one negative member. AM 0.556 borderline + dual deafness phenotype confirm severe consequence.
Druggability Assessment
Mechanism: charge loss from D796-D797-E794 cluster. Therapeutic: same target as D797V.
Why this matters
Feed this card to Wolfram Intelligence
Download the D797N PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.